NIH has received new funds for Fiscal Years 2009 and 2010 as part of the American Recovery & Reinvestment Act of 2009 (Recovery Act), Pub. L. No. 111-5. The NIH has designated at least $200 million in FYs 2009 – 2010 for a new initiative called the NIH Challenge Grants in Health and Science Research.

The NIH has identified a range of Challenge Areas that focus on specific knowledge gaps, scientific opportunities, new technologies, data generation, or research methods that would benefit from an influx of funds to quickly advance the area in significant ways. Each NIH Institute, Center, and Office has selected specific Challenge Topics within the broad Challenge Areas related to its mission. The research in these Challenge Areas should have a high impact in biomedical or behavioral science and/or public health. 

The application due date is April 27, 2009.

Broad Challenge Areas and Specific Challenge Topics

Note: Those marked with an asterisk (*) are the highest priority topics; however, applicants may apply to any of the topics.

For NIAAA, the Challenge Topics are: 01 - 09, 11, 14, 15. 

(01) Behavior, Behavioral Change, and Prevention
 

01-AA-101*      Identifying Phenotypic Markers for Positive Behavior Change.  Identify reliable, robust intermediate phenotypic markers (using cognitive neuroscience and behavioral economics) that can be used to personalize approaches to support positive health behavior change in the near term. Examples include behavioral disinhibition, delay discounting, heart rate variability and implicit cognition. Contact: Dr. Mark Willenbring, 301-443-1208, mlw@niaaa.nih.gov

01-AA-102*      Functional Roles of Neuroimmune Factors in Mediating Behavior.  Neuroimmune factors significantly impact both normal brain functions and a variety of neurological and behavioral disorders. Emerging data suggest that physiological functions of neuroimmune factors, such as cytokines and chemokines, are not restricted to mediating neuroinflammatory responses but may be considered as a new class of neurotransmitter, neuromodulator, or neurohormone in the brain. This paradigm shift offers a new framework to understand the roles of neuroimmune factors in a variety of behavioral conditions such as excessive drinking, anxiety, depression, etc. Contact:  Dr. Antonio Noronha, 301-443-7722, anoronha@mail.nih.gov

01-AA-103*      Capturing Social Network Information for Groups at High Risk for Negative Health Behaviors. Emerging evidence indicates that social networks influence health behaviors such as eating habits, alcohol consumption, and smoking. Research in this area is needed to enhance existing methodologies and/or devise novel methods that will capture social network information among groups at heightened risk for particular negative health behaviors. The ultimate public health goal is to use this information to influence behavioral choices and improve health outcomes. Contact: Dr. Mark Willenbring, 301-443-1208, mlw@niaaa.nih.gov

01-AA-104       Computational Brain Modeling of Alcohol-Seeking and Drinking Behavior.  Alcohol use disorder is a complex disease involving a variety of neurotransmitter, neuromodulator, and neurohormonal systems and various intracellular networks. It is, most likely, that targeting a combination of sites within these systems and networks will be essential in developing effective medications. These systems and networks are part of neurocircuits responsible for different aspects of alcohol addiction, including craving, reward, protracted abstinence symptoms, impaired control, tolerance, inhibition, and executive function. Research is encouraged to develop system computer modeling of these neurocircuits as an important step forward in understanding alcohol seeking and drinking behavior and identifying multiple targets in the brain for the development of effective medications.  Although creating a valid computer model of this kind of biological network requires an immense effort, the payoff would be enormous.  Correctly predicting the linked effects of changes of various neurotransmitter and neuromodulator systems and intracellular networks within and across these neurocircuits will provide a solid foundation for treating problematic drinking. Contact: Dr. Mark Willenbring, 301-443-1208, mlw@niaaa.nih.gov

01-AA-105       Mechanisms of Behavior Change.  This initiative will support research to better understand the mechanisms underlying the initiation and maintenance of behavior change among heavy drinkers, by modeling the relationship among neurophysiological, psychological and social factors involved (modeling across scale).  This will lead in turn to new methods to support positive change, moving beyond interventions that consist primarily of education and persuasion.  Research is needed on both treatment-seeking and community-dwelling populations, examining the mechanisms and processes involved in initiating change, including predictors of success or failure as well as processes that underlie maintenance of change or relapse.  Research needs to explicitly examine mechanisms, and may use statistical modeling techniques such as structural equation modeling, but priority will be given to projects that experimentally manipulate potential mediators of change.  Development of novel technologies, experimental approaches and mathematical modeling methods is also encouraged.  Research projects that incorporate or integrate two or more disciplines of research or levels of analysis such as psychological, neurophysiological, or genomic are of particular interest. Consideration will also be given to exploratory or developmental projects that are expected to help refine hypotheses and generate pilot data. Contact: Dr. Mark Willenbring, 301-443-1208, mlw@niaaa.nih.gov

01-AA-106       Alcohol’s Effect on Adolescent Brain Development.  Adolescence is a period of rapid brain growth and neural remodeling, particularly in the prefrontal cortex, an area which subserves “executive” functions such as cognitive flexibility, self-regulation and the evaluation of risk and reward.  Two major developmental brain processes, myelination and synaptic pruning, continue to occur throughout adolescence.  In addition to these structural changes, neurotransmitter systems undergo substantial modification.  Concurrently, there is a significant escalation in drinking during the adolescent period.  Of particular concern are the widespread occurrence of episodes of binge drinking and intoxication, and the association of adolescent alcohol exposure with later alcohol abuse and dependence.  Research is encouraged to determine whether alcohol interferes with normal adolescent brain development at the cellular and molecular level, and, if so, how it affects patterns of brain connectivity, that may influence drinking behavior and the emergence of alcohol-related disorders. Contact: Dr. Ellen Witt, 301-443-6545, ewitt@mail.nih.gov

01-AA-107      Alcohol, Brain Development, and Adolescent Decision Making.  Alcohol remains the most commonly abused substance among adolescents.  However, little is known about cognitive, emotional and social processes that may contribute to high rates of adolescent drinking and how alcohol use in turn may affect these processes.  During adolescence, developing brain systems underlying cognitive, emotional, and social behaviors develop at different rates.  This asynchronous maturation of intellectual and emotional skills and their underlying neural substrates may help explain age and individual differences in judgment, decision making, sensation seeking, and risk taking which make adolescents vulnerable to developing alcohol abuse and dependence.  Research is needed to determine differences between adolescent and adult decision-making processes and reward-based learning as they relate to alcohol drinking behavior, and to determine the effects of adolescent drinking on the development of decision-making processes, reward-based learning and their underlying neural substrates. Contact: Dr. Ellen Witt, 301-443-6545, ewitt@mail.nih.gov

01-AA-108     Alcohol, Pubertal Hormones, and Sex Differences in Alcohol Abuse and Dependence.  Between the ages of 12 and 17, adolescent males and females have similar patterns of alcohol use and similar prevalence of alcohol abuse and dependence.  By late adolescence, however, sex specific patterns begin to emerge, with females exhibiting fewer drinking days in the past month, fewer episodes of heavy drinking, and lower prevalence of alcohol abuse and dependence relative to males. Substantial changes in brain biology, physiology, and architecture occur during the transitions from pre-adolescence through adolescence and into young adulthood.  The hormonal changes of puberty also affect the developing brain and may help explain the disparate drinking trajectories of boys and girls.  Recent evidence suggests that an increase in gonadal steroids and stress response hormones during puberty may influence the structural and functional remodeling of the brain. Thus, hormonal mechanisms, such as activation of reproductive hormones, stress responses, and their effects on brain developmental processes could explain the observed sex differences in alcohol drinking patterns during puberty.  With brain development and puberty proceeding at the same time as rapid escalation in alcohol use, it is important to consider potential effects of alcohol on the interaction between pubertal hormone changes and adolescent neurodevelopmental processes and the implications of alcohol-induced changes in these processes on sex differences in future alcohol use and misuse. Two-year studies are needed to investigate the degree to which hormonal changes at puberty interact with neurodevelopmental processes to promote sex effects in alcohol use and misuse, and the effects of alcohol on these interactive processes.  Contact: Dr. Ellen Witt, 301-443-6545, ewitt@mail.nih.gov

01-AA-109    Alcohol and Chronobiology.  Recent research has demonstrated the potent effect of clock genes, those involved in regulation of circadian rhythms, in addictive behavior.  Mutant or variant alleles of clock genes can alter incentive salience and modify the vulnerability of risk for alcohol dependence.  Conversely, environmental disruption can create acute, or in the case of fetal alcohol exposure, long term disruption of circadian function and stress.  This in turn can enhance alcohol self administration.  Such observations clearly implicate circadian function as a potential factor in alcohol dependence.  Research that characterizes the consequences of clock gene knock-outs or knock-ins for alcohol consumption would aid in establishing the link between clock genes and risk for alcohol abuse. Contact:  Dr. Lindsey Grandison, 301-443-0606, lgrandis@mail.nih.gov

01-AA-110     The Impact of Alcoholic Beverage Container Labels on Drinking-related Behaviors and Beliefs.  Unlike most consumable products, alcoholic beverage containers carry little or no information about ingredients, calories and serving sizes. Researchers and consumer groups have pushed the importance of labels for educating the public about serving sizes in order to help consumers avoid unwanted side effects, stay within the boundaries of moderate consumption and make healthy dietary choices. For instance, while a single serving of wine per day could convey benefits for cardiovascular health, two or more servings per day can increase the odds of breast cancer and other cancers.  Some malt beverages contain as many calories as some chocolate bars. Presumably, such information would be of value to consumers and could influence their drinking habits and beverage choices.  Despite the logical appeal of placing detailed labels on beverage containers, it remains unclear what, if any, impact such labels might have on alcohol-related attitudes, beliefs and behaviors. Further, it remains unclear what information should appear and where. Innovative developmental studies to determine the impact of alcoholic beverage container labels on drinking-related behaviors and beliefs are encouraged. Contact: Dr. Aaron White, 301-451-5943, whitea4@mail.nih.gov

01-OD(OBSSR)-101*      Tools for studying cultural phenomena. Development of new tools for: the measurement of culturally-shared mental phenomena (e.g., representations, scripts, prejudices); studying mechanisms by which these phenomena are transferred and adapted across individuals; and advancing research on the distribution and transmission of cultural phenomena within populations. Contacts: Dr. Christine Bachrach, 301-496-9485, cbachrach@nih.gov; NIAAA Contact: Dr. Marcia Scott, 301-402-6328, mscott@mail.nih.gov

(02) Bioethics

02-OD(OSP)-103*     Ethical Issues Associated with Electronic Sharing of Health Information.  The development of an electronic health information infrastructure and the sharing of health information for patient care and research offer enormous promise to improve health care and promote scientific advances.  However, the broad sharing of such data raises numerous ethical issues that may benefit from additional studies (e.g. those related to privacy and confidentiality).  Examples include studies to assess risks associated with health information technology and the broad sharing of health information for research, and novel approaches for mitigating them. Examination could also include analysis of current oversight paradigms and suggestions for enhancements, as well as assessments of how privacy risks may change in the future. OD(OSP) Contact:  Abigail Rives, 301-594-1976, rivesa@od.nih.gov; NIAAA Contact:  Dr. Patricia Powell, 301-443-5106, ppowell@mail.nih.gov

02-OD(OSP)-104*     Ethical Issues in the Translation of Genetic Knowledge to Clinical Practice.  Genetics and genomics have great promise for the development of personalized medicine, yet the ethical, legal and social implications of both the research and application of genetic and genomic knowledge and technology are far reaching. Studies are needed to better understand the factors that influence the translation of genetic information to improved human health and the associated ethical issues. Examples of studies include those to address ethical issues related to broad sharing and use of new genetic information and technologies for research to improve human health, human subjects protection in genetic and genomic research, the identifiability of genetic/genomic information and how our understanding of identifiability is evolving, return of research results and incidental findings to subjects, alternative models of informed consent for broad data sharing for research, and the impact of intellectual property (IP) issues on development of new technologies.  OD(OSP) Contact:  Abigail Rives, 301-594-1976, rivesa@od.nih.gov; NIAAA Contact:  Dr. Patricia Powell, 301-443-5106, ppowell@mail.nih.gov

(03) Biomarker Discovery and Validation
 

03-AA-101     Identification of Intermediate Phenotypic Markers of Alcohol Use Disorders. Alcohol use disorder is a heterogeneous disease resulting from complex interactions of genes and environment to yield a range of phenotypes.  Because of this heterogeneity, available treatments work for some, but not, all individuals.  Being able to distinguish subtypes will advance personalized medicine by identifying those who respond favorably to specific treatments. One approach to identify subgroups is to measure intermediate phenotypic markers. These markers are found in groups that share a common neurobiology, usually controlled by only a few genes. Alcohol researchers have begun to investigate a variety of intermediate phenotypes using basic behavioral, clinical, and neuroscience approaches. Examples include P300 event-related potential, facial flushing syndrome, pathologic anxiety as measured by low-voltage alpha electroencephalogram, and aspects of disinhibition as determined by impaired prefrontal cognitive function.  However, the discovery of more sensitive, specific markers is needed to more clearly delineate complex alcoholic phenotypes. Research is encouraged in promising areas such as electrophysiology, social and cognitive neuroscience, behavioral economics, neuroimaging, and subjective and physiological responses to alcohol. Contact: Dr. Mark Willenbring, 301-443-1208, mlw@niaaa.nih.gov

03-AA-102     Validating Human Laboratory Models as Predictors of Clinical Efficacy.  Developing medications is a long, costly process with a low probability of success for any single agent.  In particular, human clinical trials are particularly time consuming.   Therefore, development and validation of screening procedures that are predictive of performance in clinical trials are needed.  Currently, there are numerous promising compounds in the developmental pipeline, but there are no proven ways to select which of them should be tested clinically.   Development and validation of screening paradigms using human laboratory procedures offers one potential avenue for screening novel compounds. To be a successful screening model, clinical indicators from the human lab models should be predictive of treatment outcome. Several human lab paradigms currently exist, including cue reactivity, alcohol self-administration and alcohol administration models. Examples of clinical indicators used in these models are craving, physiological measures (heart rate, blood pressure, skin conductance), self-administration measures, motivation to drink, alcohol reinforcing behavior, and impulsive behavior.  Currently, none of these indicators have been shown to reliably predict clinical performance.  Research is encouraged to discover new indicators that are predictive of clinical performance. Validation of these indicators will require both “upstream” validation by examining their predictive power in human clinical trials, as well as “downstream” validation by examining the relationship between performance testing various animal models with human laboratory indicators. Contact: Dr. Mark Willenbring, 301-443-1208, mlw@niaaa.nih.gov

03-AA-103     Molecular Markers of Alcohol-induced Tissue Injury.  High-throughput bioinformatic investigations of alcohol's impact on, for example, the epigenome, transcriptome, proteome, metabolome, etc. are needed to inform our understanding of the mechanisms involved in alcohol-induced injury to adult and fetal tissues.  Additionally, these approaches have the potential to reveal candidate biomarkers of alcohol-induced pathology and alcohol exposure.  Research is sought to develop diagnostic biomarker signatures of alcohol consumption and alcohol-induced organ damage. Contact: Dale Hereld, M.D., Ph.D. 301-443-0912, hereldd@mail.nih.gov or Kathy Jung, Ph.D., 301-443-8744, jungma@mail.nih.gov

03-OD(OBSSR)-101*     Developing high-throughput biomarker assays from finger-stick dried blood spots.  Develop, using finger-stick dried blood spots, novel high-throughput biomarker assays, to identify lipids, proteins, metabolites, and genetic information to expand the array of available biomarkers for use in large community-based biosocial surveys.  OBSSR contact:  Kay Wanke, 301-435-3718, wankek@od.nih.gov; NIAAA Contact:  Marcia Scott, Ph.D., 301-402-6328, mscott@mail.nih.gov

(04) Clinical Research
 

04-AA-101*     Medication Development for Hepatic Fibrosis.  Alcohol and infectious disease induced hepatic fibrosis affects millions of patients worldwide and remains an unresolved challenge for clinicians.  Given the morbidity/mortality associated with this disease, there is an urgent need for translation of emerging antifibrotic molecules into effective therapies.  Expediting clinical trials for compounds that have successfully undergone preclinical studies has the potential to make much needed medications available and reduce the need for liver transplantation. Contact:  Samir Zakhari, Ph.D Director, Division of Metabolism and Health Effects, 301-443-0799, szakhari@mail.nih.gov

04-AA-102     Use of in silico techniques to develop compounds to treat alcohol dependence.  Recent advances in computational software and hardware have revolutionized the process of drug discovery.  This initiative will support the use of in silico computational methods to facilitate the development of new compounds for the treatment of alcohol dependence.  In silico modeling may be used for all aspects of the drug discovery and drug design process including identifying and characterizing brain targets of alcohol effects for possible binding sites; designing and generating candidate molecules; virtual screening of compound libraries to identify lead structures; optimizing lead compounds; as well as use of in silico models to predict absorption, distribution, metabolism and excretion properties of molecules to address early toxicity issues.  The goal is to streamline and expedite the traditional process of drug development and produce novel compounds for the treatment of alcohol dependence. Contact: Dr. Mark Willenbring, 301-443-1208, mlw@niaaa.nih.gov

04-AA-103     Novel Models of Service Delivery.  Fewer than 10% of people with alcohol use disorders ever receive professional treatment. Furthermore, most specialty treatment programs have not implemented NIAAA-funded research findings on behavioral or pharmacologic treatment.  Thus, the public has no effective access to research-based treatment.  Obviously, research on implementation will be important for increasing adoption of such findings in specialty treatment programs, but it is not sufficient. Two year studies are encouraged to develop and test additional models of care.  Key to the impact of this research is that these models will need to be accessible, affordable, culturally sensitive, and acceptable to the patients. Research should also examine strategies for integrating prevention and treatment services into other service components to enhance access including medical, mental health care, employment and social services, and criminal justice. Enhanced collaboration among the various treatment providers and treatment sectors should also be emphasized. Given the small percentage of individuals with alcohol use disorders who receive treatment, it is important that future research focus on personal barriers (i.e. stigma, denial, etc.) as well as on organizational barriers (availability, costs, etc.) that affect treatment access.  It is important that this research examine the unique barriers faced by at-risk populations.  Also key to addressing the chronic nature of this illness will be studies that examine models that support long term access for individuals who may need additional help, such as booster sessions or rapid re-entry into care rather than waiting until a relapse has become serious enough to warrant re-treatment.  Contact: Dr. Mark Willenbring, 301-443-1208, mlw@niaaa.nih.gov

04-AA-104     Disease Management of Chronic or Relapsing Illness.  About 30% of people with a lifetime diagnosis of alcohol dependence have a chronic form of the illness; those with more than one episode have an average of five episodes.  Yet our models are almost all time-limited, and focus exclusively on relapse prevention among people who have already stopped drinking. Two year research studies are sought to determine how services should most effectively be structured and financed in order to provide effective care. Since many of these individuals have serious co-morbidities, research care models should integrate care for different disorders, co-locate them, or coordinate them.  In addition, many chronically ill people are unable to make use of current treatments because they have sensory or cognitive deficits and research should also address how to provide care in these situations.  Research is also sought to develop and test alternative modes of care delivery, especially tele-medicine, telephone care, internet, and toll-free telephone numbers. Contact: Dr. Mark Willenbring, 301-443-1208, mlw@niaaa.nih.gov

04-AA-105     Adaptive Screening and Intervention Technology.  Decisional models are being developed to characterize the interaction of prevention and treatment modalities for at-risk and HIV infected individuals in order to prevent acquisition, transmission, and progression of infections resulting in death. Research is encouraged to explore these models more systematically and identify choice points in interventions where optimal prevention and treatment strategies can be put into place. The goal is to develop and test models tied to specific end points (antiretroviral treatment failure, mortality, cost, etc) using appropriate Operations Research methodologies to prioritize among multiple alcohol interventions, construct portfolios of alcohol interventions that deliver the maximum value, and consider capacity constraints in the infrastructure, and consider investments to reduce those capacity constraints within the portfolio of possible interventions.  This approach calls for development of a broader systems science that focuses on optimization and is a natural extension of operations research. Contact:  Dr. Kendall Bryant, 301-402-9389, kbryant@mail.nih.gov

04-NR-101  Integrating Cost-Effectiveness Analysis into Clinical Research This initiative calls for the inclusion of rigorous cost-effectiveness analysis in the design and testing of new and innovative interventions as well as existing interventions with demonstrated effectiveness.  Cost-effectiveness research will provide accurate and objective information to guide future policies that support the allocation of health resources for the treatment of acute and chronic diseases across the lifespan. Contact: Dr. Linda Weglicki, 301-594-6908, weglickils@mail.nih.gov; NIAAA Contact: Contact: Dr. Mark Willenbring, 301-443-1208, mlw@niaaa.nih.gov

(05) Comparative Effectiveness Research

05-AA-101*   Innovative Analyses of Existing Clinical Datasets. Typically secondary analyses of administrative and clinical data have been utilized for multiple objectives that include estimating incidence and prevalence of alcohol use and alcohol disorders, estimating treatment needs, developing health policy, testing clinical hypotheses, and performing meta-analyses that may contribute insights on the comparative effectiveness of behavioral and pharmacological therapies.  Under this Challenge Grant initiative, researchers are encouraged to use secondary data analyses in methodologically innovative ways. An example is the use of cross-design synthesis to standardize and compare clinical data collected by different methods, thereby expanding the scope of knowledge on comparative treatment effectiveness. Another example is evaluation of the impact of new statistical models and methods on treatment effectiveness outcomes, for instance, comparing the relative impact of linear models and dynamic models on clinical trial outcomes.  Both clinical and health services research proposals based on secondary analyses are invited under this initiative.    NIAAA Contact: Dr. Mark Willenbring, 301-443-1208, mwillenb@mail.nih.gov

05-AA-102*   Adaptive Designs and Person-Centered Data Analysis for Alcohol Treatment Research. Simple trials comparing two treatments, or a treatment and a control condition, are essential in determining the efficacy of various treatments. However, such studies often do not answer questions of particular import to clinicians, who have to make a series of decisions in the same patient based upon response to initial and subsequent treatment. Adaptive designs offer a potential solution, but they are methodologically complex, are difficult to implement and require large numbers of subjects. Similarly, statistical analyses using variable-centered approaches (e.g., comparison of means) may miss important variability in outcomes, especially since statistical assumptions (e.g. normality) are routinely violated. Person-centered approaches such as trajectory analysis may offer an alternative that better captures differences in outcomes and also is more clinically intuitive. Research and development are needed to further develop such approaches and especially to make them easier to use. Also, additional new approaches are needed in order to speed the process of comparing effectiveness of different treatments. NIAAA Contact: Dr. Mark Willenbring, 301-443-1208, mwillenb@mail.nih.gov.

05-AA-103* Use of Innovative Technologies in Alcohol Treatment Research. Although progress has been made to standardize methods for measuring alcohol consumption in research on treatment of heavy drinkers, the best methods currently available still rely on retrospective accounts. Recent research comparing these interview methods with interactive voice response (IVR) has demonstrated that the interviews have reasonable validity for overall consumption, but day-to-day variability does not adequately characterize true consumption. More research is needed on the best type of technologies to use (IVR, pagers, etc.) and how best to integrate it into clinical trials. A related challenge has been standardizing behavioral interventions through the use of extensive training, monitoring and supervision. However, substantial variability exists with regard to the outcome of individual therapists. In addition, these therapies are not feasible to implement in community settings. Research is needed to develop and validate computerized behavioral interventions that can be used in clinical trials, especially for pharmacotherapy trials, and that offer easy adoption in the community. NIAAA Contact: Dr. Mark Willenbring, 301-443-1208, mwillenb@mail.nih.gov.

(06) Enabling Technologies

06-AA-101     Analysis of Alcohol's Effects on Cell Behavior.  Projects are sought for the development of new advanced approaches such as techniques to image intact tissue slices, and three-dimensional (3D) cell culture systems that could provide the spatial and temporal dynamic pictures of the patho-physiology and dys-functioning of living cells in the presence of alcohol. Contact: Dr. Svetlana Radaeva, 301-443-1189, sradaeva@mail.nih.gov

06-AA-102    New Animal Model Systems for Alcohol Research.  Lack of good model systems has been a major obstacle in our understanding of alcohol-induced disorders, such as liver fibrosis, fetal alcohol spectrum disorders, and cardiomyopathy.  The goal of this initiative is to develop new model systems, including animal models, cell culture, and in vitro biochemical or other systems, will provide critical tools and new perspective in our understanding and treatment of alcohol-induced disorders.  Examples include zebrafish and planaria to study embryonic development and liver regeneration, mouse embryo and ES cells to understand FASD-related mechanisms, and canine models to study alcohol-induced cardiomyopathy. Contact: Dr. Max Guo, 301-443-0639, qmguo@mail.nih.gov

06-AA-103     Computational Models for Tissue Injury.  Recent developments in flow cytometry utilize a FACS Aria flow cytometer, which allows the simultaneous determination of as many as 18 different parameters in single cells.  Using this technology, it is possible to simultaneously quantitate a large variety of cellular constituents in the same cell.  For example, in a single cell one can simultaneously measure early apoptosis, late apoptosis, molecules in the caspase cascade that lead to apoptosis, key molecules of canonical signaling pathways (e.g., PI3 kinase, Akt, mTOR, BCL 2, etc.), and numerous transcription factors (e.g., Oct 3/4, Sox 2, Nanog, etc.).  By using Bayesian statistics and advanced computer programs, we can establish models of various signaling pathways that are affected by alcohol.  Research to develop computational models is sought as they offer a promising integrative approach to alcohol research. Contact: Dr. Samir Zakhari, 301-443-0799, szakhari@mail.nih.gov

06-AA-104     Systems Biology Approach for the Characterization of Immune Function.  Research is encouraged that takes a systems biology approach to study the effects of alcohol on immune function, by measuring a panel of immune effectors.  Such an approach includes quantitative profiling and validation of pro- and anti-inflammatory cytokines, chemokines and their receptors, (cell surface and secreted) and neuroendocrine hormones at different stages of liver disease or immune function impairment using analytical techniques with multiplex capability.  The goal is to provide bases for diagnostic biomarkers and for designing intervention strategies.  This approach also pertains to the combination of alcohol and infection with HCV or HIV/HCV.  Contact:  Kathy Jung, Ph.D., 301-443-8744, jungma@mail.nih.gov or Joe Wang, Ph.D., 301-451-0747, Wangh4@mail.nih.gov

06-AA-105     Monitoring the Blood Alcohol Concentration in the Magnetic Resonance (MR) Imaging Environment.  The understanding of alcohol’s effects on brain function has benefited from the use of brain imaging technology such as magnetic resonance imaging (MRI). However, to determine more precisely the effects of alcohol on brain function (such as cerebral blood flow) and behavioral performance during brain imaging (such as working memory or a simulated driving task), it is necessary to know the exact blood alcohol level moment to moment over the ascending and descending portions of the alcohol curve. This will allow researchers to track changes in brain function and behavior and to directly relate them to the alcohol concentration in individual research subjects. But the MR imaging environment is sensitive to magnetic susceptibility artifacts that may be caused by the metal in instruments used to monitor alcohol concentration when in close proximity to the MR scanner. This initiative seeks development of a MR-compatible device, validation of its use and determination of the effects of the instrument on the brain images acquired. The outcome, which is possible in two years with a directed effort, is the ability to continuously monitor the changes in blood alcohol concentration during brain imaging experiments.  Contact: John Matochik, Ph.D., 301-451-7319, jmatochi@mail.nih.gov

06-AA-106     Technology Development for Analysis of Alcohol-Related Neural Circuits.  Technology has vastly expanded our understanding of neuroscience in the last decade. However, there are still limitations to our understanding of how neural circuits and neural plasticity integrate to produce complex behaviors. Multi-unit recordings, optogenetics and other sophisticated tools for neuroscience research have recently been developed, yet these tools have been relatively underutilized in neurobiological studies examining alcohol’s effects on the brain. Studies using these or other novel techniques for neural circuit analysis in alcohol research would greatly increase our understanding of how various brain circuits and regions interact to influence alcohol consumption, withdrawal and relapse.  The application of new technologies to determine the relative contribution of different brain circuits (e.g., cognitive, stress, homeostatic, and reward circuits) to stress-induced relapse will aid in the understanding of alcohol addiction and the development of new therapeutic targets for alcohol relapse. Contact: Dr. Tom Greenwell, 301-443-1192, greenwellt@mail.nih.gov

06-AA-107     Molecular Imaging of Dendritic Spines in Response to Alcohol Exposure.  Dendritic spines are the major postsynaptic compartments for excitatory synaptic transmission. Their structures and densities are dynamically influenced by synaptic activity, neurological and psychological disorders, and addictive drugs. Limited studies have demonstrated that acute and chronic alcohol exposure changes both the size and density of dendritic spines in various brain regions. However, little is known about the molecular dynamics that underlie these changes. Recent advances in live-cell imaging techniques, which combine fluorescent probes and optical recording methods, allow visualization of dynamic changes of dendritic spines and associated molecules in vitro and in vivo. Research applying advanced imaging techniques, combined with biochemical, functional, and behavioral analysis, provides an opportunity to improve our understanding of alcohol-induced alterations in the structure and density of dendritic spines.  Contact: Dr. Changhai Cui, 301-443-1678, Changhai@mail.nih.gov

06-AA-108     Innovative Technologies for Drinking Pattern Analysis. Most data on drinking patterns is based on self-reports of daily, weekly and/or monthly consumption. Studies are sought which utilize innovative methodologies/technologies such as  ecological momentary assessment to obtain more detailed information about drinking patterns over the course of a day and how these patterns relate to physiology, context and other biological and environmental factors. Such data can also identify subgroups of individuals whose drinking patterns fall across the spectrum of alcohol use (e.g. initiation, escalation to harmful use, dependence). It can also be used to inform interventions. Contact:  Dr. Marcia Scott, 301-402-6328, mscott@mail.nih.gov

06-AG-101*       Neuroscience Blueprint: Development of non-invasive imaging approaches or technologies that directly assess neural activity.  This could include research on imaging neuronal electrical currents, neurotransmitter changes and/or neuronal/glial cell responses to brain circuit activation.  This scientific area could be advanced by improvements/refinements in existing imaging technology or use of emerging technology that could be developed in two years.  The outcome of this challenge could have high impact by connecting the system-level, large population view afforded by fMRI with the cellular processes and responses that contribute to the BOLD-fMRI signal.  Two-year challenge projects could stimulate the development of human brain imaging techniques that link cell activity underlying neural communication to the structure and function of brain circuits, and could complement other brain connectivity imaging modalities.  Contact: Bradley Wise, 301-496-9350, wiseb@nia.nih.gov. NIAAA Contact: Dr. Antonio Noronha, 301-443-7722, anoronha@mail.nih.gov

06-OD-101*       Development of new tools and technologies to interrogate human mitochondrial function in vivo.  These tools would include methods to manipulate human mitochondrial structure and activity, as well as novel imaging techniques to monitor and measure human mitochondrial function or dysfunction in healthy and diseased tissues.  Contact: Phil Smith (NIDDK), 301-594-8816, smithp@mail.nih.gov; NIAAA Contact Dr. Samir Zakhari, 301-443-0799, szakhari@mail.nih.gov

06-OD(OBSSR)-101*    Using new technologies to improve adherence.  New and innovative technologies to improve patient adherence to prescribed medical regimens and utilization of adherence-enhancing strategies in clinical practice would greatly enhance the health impact of efficacious treatments and preventive regimens.  This challenge invites the development of new technologies to change patient and provider behaviors to improve adherence.  OBSSR contact: Lynn Bosco, 301-451-4286, boscol@od.nih.gov; NIAAA Contact:  Marcia Scott, Ph.D., 301-402-6328, mscott@mail.nih.gov

06-DK-101*        Development of cell-specific delivery systems for therapy and imaging.  Develop non-viral strategies for cell-specific delivery of pathway-interactors and molecular probes. These new molecular complexes could allow delivery of cell-penetrating agents for the study of disease pathways, the imaging of tissue mass and disease progression, or the development of tissue-specific therapeutics.  Contact: Dr. Olivier Blondel, 301-451-7334, blondelol@mail.nih.gov; NIAAA Contact:  Dr. Samir Zakhari, 301-443-0799, szakhari@mail.nih.gov

06-MD-101* Development of Telehealth Tools to Promote Health and Connect At-Risk Youth to the Health System via Low-Cost, Mobile, and Wireless Technologies. NCMHD is interested in the development of telehealth messages utilizing various forms of technology, aimed at high-risk youth as well as innovative culturally and linguistically appropriate media strategies for connecting at-risk youth with the healthcare system. Dr. Nathaniel Stinson, 301-402-1366, stinsonn@mail.nih.gov. NIAAA Contact: Dr. Mark Willenbring, 301-443-1208, mlw@niaaa.nih.gov

(07) Enhancing Clinical Trials
 

07-OD(OBSSR)-101*     Improving and/or assessing external validity in randomized clinical trials (RCTs). The practice of conducting RCTs with volunteer samples recruited from patients in clinical or community settings limits the generalizability of results, a critical problem for comparative effectiveness research.  Research is needed to develop scientific tools for improving and/or assessing the external validity of RCT results to known populations, including methods for applying probability sampling in the identification and recruitment of RCT participants, measuring biases in RCT participant pools, and accounting for such biases in the analysis of RCT results. OBSSR contact: Dr. Ronald Abeles, 301-496-7859, abelesr@od.nih.gov; NIAAA Contact:  Dr. Marcia Scott, 301-402-6328, mscott@mail.nih.gov

07-NS-101*      Developing technology to increase efficiency and decrease cost of clinical trials.  Clinical trials are becoming increasingly expensive, and many US patients are unwilling to enroll, which has led to delays in trial completion and further cost increases.  The challenge is to develop and test affordable, technologies to enable remote, centralized monitoring of physiologic, behavioral and neurologic indices as well as study medication compliance, and adverse effects in clinical trials.  These technologies should provide opportunities to enhance efficiency in clinical trials, as well as to collect more “real life” data. Contact: Dr. Emmeline Edwards,  301-496-9248, ee48r@nih.gov; NIAAA Contact: Dr. Mark Willenbring, 301-443-1208, mlw@niaaa.nih.gov

(08) Genomics
 

08-AA-101     Inflammation and Alcoholic Liver Disease.  Research is sought to study the relationship between alcoholic liver disease and gene polymorphisms affecting theTLR4 signaling complex (e.g., TLR4, MD2, and LBP) and pro- and anti-inflammatory cytokines, chemokines and their receptors.  Understanding of genetic variations of these key inflammatory factors and their association to the susceptibility to alcohol-related diseases will provide a basis for better diagnosis and optimal design of treatment options.  Contact:  Dr. Joe Wang, 301-451-0747, Wangh4@mail.nih.gov

08-AA-102     Genome Wide Association Studies of Alcohol Dependence.  The genetic contribution to the development of alcohol dependence has been established by twin, adoption and family studies. In addition, environmental factors play a major role in the development of this disorder. Genome Wide Association Studies (GWAS) provide a powerful approach to pinpointing the genes or gene variants that contribute to risk for developing the disorder.  However, GWAS requires a large and well-characterized sample. This initiative will provide two-year funding for genotyping and data analysis of existing samples of complex behavioral disorders, including alcohol dependent subjects and matched controls that are suitable for GWAS. Contact:  Dr. Abbas Parsian, 301-443-5733, parsiana@mail.nih.gov

08-AA-103     Collaborative Cross for Phenotyping of Behaviors.  The impact of genes on behavior has been established and shown to significantly influence susceptibility to mental health disorders and other behaviors such as those that influence risk for alcohol dependence.  Current approaches have localized chromosome regions, or quantitative trait loci (QTL), that are associated with increased risk for alcohol dependence.  However, within these QTLs there are numerous potential genes and it remains unclear which ones(s) is responsible.  Research is sought to develop mouse lines with increased genetic variability and complexity, more similar to humans, and to perform behavioral phenotyping on these animals to identify the specific genes contributing to physiological or behavioral disorders, including those associated with risk for alcoholism.  Contact person:  Dr. Lindsey Grandison, 301-443-0606, lgrandis@mail.nih.gov

08-AA-104      Regional Central Nervous System (CNS) Gene Expression.  Response to an environmental challenge or to alcohol exposure results in significant changes in gene expression that leads to neuroadaptation.  Recent advances in microarray technology allow rapid and widespread characterization of regional changes in gene expression in brain areas such as the Bed Nuclei of the Stria Terminalis (BNST), prefrontal cortex, raphe nucleus, as well as CNS areas commonly involved in alcohol abuse.  Research is needed to fully characterize the gene expression profile in response to stress or alcohol to permit identification of responsive gene networks that mediate the change in behavior.  Such studies would be a valuable resource for determining the impact of stress on alcohol related behaviors, reward sensitivity and neurocircuitry of consumption.  Subsequent gene network analysis would permit identification of the genes involved in orchestrating behavioral response. Contact:  Dr. Lindsey Grandison, 301-443-0606, lgrandis@mail.nih.gov

08-AA-105      Epigenetic regulation of synaptic adaptation in alcohol dependence, withdrawal and relapse.  Alcohol dependence involves complex synaptic remodeling with associated changes in receptor trafficking, local mRNA translation, protein turnover, and gene expression. Increasing evidence suggests that stable gene expression and synaptic structure and function changes associated with drug and alcohol addiction are mediated in part by epigenetic mechanisms. This initiative encourages 2-year projects to: 1) determine the role of epigenetic factors in regulating synaptic plasticity and adaptation; and 2) identify genes under epigenetic control in acute and chronic alcohol exposure. Such research is expected to reveal molecular substrates mediating long-term synaptic changes in the brain that underlie alcohol addiction and relapse, and inform potential therapeutic targets to block the transition to, or even reverse, the alcohol dependent state. Contact:  Dr. Qi-Ying Liu, 301 443-2678, liuqiy@mail.nih.gov

08-AA-106     Genome Wide Association Studies of Drinking Patterns and the Etiology of Alcohol Problems. There are many well-characterized populations from studies which have or are still collecting information about drinking patterns and the etiology of alcohol problems including abuse and dependence.  These studies include both prospective studies with children and adolescents as well as studies of adults that have been followed for many years. Projects could collect DNA from individuals in these studies and conduct gene association studies among subgroups of these individuals to expand understanding of genetic and environmental contribution to drinking patterns. Contact:  Dr. Marcia Scott, 301-402-6328, mscott@mail.nih.gov

(09) Health Disparities
 

09-AA-101     Factors Influencing Effectiveness of Alcohol Treatment Among Minority and At-Risk Populations. Despite the increased awareness of the diversity of individuals with alcohol use disorders, research has tended to focus more on differences in socioeconomic status and insurance coverage as it impacts access to care.  Even apart from access, little is known about the relative effectiveness of treatment among minority and at-risk populations.  A shift in focus is needed to one that examines diversity within groups and how that may influence disparity (Thurman & Edwards, 2007). The initial priority then is to examine the extent to which socioeconomic status interacts with race, ethnicity, gender, sexual orientation, age, and physical and mental disabilities and to determine the impact that these factors have on help seeking, availability and access, and the quality and appropriateness of care. For example, the Hispanic population is rapidly growing, and in some areas of the country constitutes a majority.  Yet there are few if any studies about treatment and provision specifically to this population.  Other groups not well studied are those who are physically impaired (such as deaf or hearing impaired), gay-lesbian, brain-injured, suffer chronic pain, etc. As a key component of this plan, research is needed on consumer preferences and needs. Too often, untested assumptions form the basis for decisions about research questions or care provision. New models of care need to be developed and tested in order to more completely address disparities. Contact: Dr. Mark Willenbring, 301-443-1208, mlw@niaaa.nih.gov

09-MD-103* Initiating Innovative Interventions to Prevent Family Violence.  NCMHD will focus on strategies to prevent family violence including domestic and intimate partner violence and enhance behavioral research efforts that build workforce infrastructure.  The development of culturally and linguistically appropriate messages and tools, the use of non-traditional methods, along with marketing strategies are also of interest. Dr. Nathaniel Stinson, 301-402-1366, stinsonn@mail.nih.gov; NIAAA Contact: Dr. Ralph Hingson, 301-443-1274, hingson@mail.nih.gov

(10) Information Technology for Processing Health Care Data for Research

For this RFA, there is no NIAAA-specific Challenge Topic in this Challenge Area.

(11) Regenerative Medicine
 

11-AA-101     The Role of Circadian Rhythms in Alcohol-induced Organ Damage.  Acute and chronic alcohol intake can affect circadian rhythms, impacting physiological, endocrine, and behavioral functions.  Alcohol may also affect liver oscillators by altering the redox state of the cell.  Recent advances in understanding the molecular mechanisms that regulate the circadian system, particularly their connection with metabolism and metabolic disorders, have provided us new perspectives in understanding the underlying mechanisms of alcohol-induced organ damage. Further investigation is warranted.  Contact: Dr. Max Guo, 301-443-0639, qmguo@mail.nih.gov

11-AA-102     Roles of Cellular Organelles and the Cytoskeleton in Alcohol-induced Organ Damage.  Whereas molecular mechanisms by which mitochondria contribute to alcohol-induced tissue injury have been studied to some extent, the role of other cellular organelles is largely unknown. Elucidating the role of mitochondria and other cellular organelles, including cytoskeleton, is crucial for understanding the underlying mechanisms of alcohol-induced disorders.  Contact: Dr. Max Guo, 301-443-0639, qmguo@mail.nih.gov

11-AA-103     Traumatic Brain Injury.  The increasing incidence of traumatic brain injury (TBI) in soldiers returning from war zones presents an emerging health-care challenge.  In general, alcohol consumption negatively impacts recovery from trauma, e.g. hemorrhagic shock.  However, a limited preliminary epidemiological study suggests a mild protective effect for alcohol during recovery from TBI.  Studies are sought to determine the beneficial and/or harmful effects of alcohol during recovery from neurological damage or other trauma. Contact:  Dr. Kathy Jung, 301-443-8744, jungma@mail.nih.gov

11-AA-104     The Endocannabinoid System and Alcohol Pathology.  The Endocannabinoid System (ECS) is central to the development of alcohol dependence and its pathological consequences, including organ damage. The brain and liver are key targets for alcohol-induced damage, and both are sites of ECS expression and targets of its action. Therefore, studies that explore modulation of the ECS as potential new avenues for treating alcoholism, metabolic syndrome and alcoholic liver disease and its complications are encouraged. Contact: Dr. Svetlana Radaeva, 301-443-1189, sradaeva@mail.nih.gov

(12) Science, Technology, Engineering and Mathematics (STEM) Education

For this RFA, there is no NIAAA-specific Challenge Topic in this Challenge Area

(13) Smart Biomaterials - Theranostics

For this RFA, there is no NIAAA-specific Challenge Topic in this Challenge Area.

(14) Stem Cells
 

14-AA-101     Mechanisms of Stem Cell Dysregulation by Alcohol.  The ability to isolate human cord blood stem cells, animal embryonic stem cells and human/animal tissue-specific stem cells, and to manipulate and assess them using commercially available reagents provides an opportunity to examine the effects of alcohol on stem cell survival and differentiation in vitro.  Examples of appropriate studies in this area include, but are not limited to: (1) Understand how alcohol-induced changes in mitochondrial metabolism, biogenesis, death pathways, etc. affect stem cell survival and maturation; (2) Determine epigenetic changes due to alcohol exposure in stem cells and their functional consequences; and (3) Identify alterations due to alcohol in stromal cells that support stem cells and determine how these changes influence stem cell fate.  Contact: Dr. Svetlana Radaeva, 301-443-1189, sradaeva@mail.nih.gov

14-AA-102     Alcohol’s Effects on Endogenous Stem Cells.  Heavy alcohol binges reduce the amount of endogenous stem cells in the brain, especially in the hippocampus. However, it is not well understood how alcohol inhibits neural stem cell proliferation in the brain and how these effects alter function and/or behavior. Research examining the effects of alcohol on neural stem cells may shed light on alcohol’s neurodegenerative effects on the brain and the regenerative capacity of these cells. This initiative solicits projects to examine mechanisms of alcohol’s effects on neural stem cells, the impact of alcohol on stem cells in other areas of the brain such as the subventricular zone, and an examination of functional and behavioral outcomes of reduced stem cell proliferation as a result of heavy alcohol exposure. Contact: Dr. Tom Greenwell, 301-443-1192, greenwellt@mail.nih.gov

14-DK-101*        Induced pluripotent stem cells--cellular and humanized mouse models of disease.  Somatic cells, such as fibroblasts, from patients with diseases can be used to create cell lines, tissues and, perhaps, organ systems, through induced Pluripotent Stem Cell (iPSC) technology.  Such models could be used to elucidate underlying pathology of disease or screen for agents that could be used therapeutically.  Combining this approach with mouse strains able to accept multiple human tissues without rejection could provide the microenvironmental milieu to support the tissue’s physiological function within the context of the whole organism, enabling greater understanding of disease pathogenesis and providing a platform for preclinical testing of drug candidates. NIDDK Contact: Dr. Dan Wright, 301-594-7717, wrightdan@mail.nih.gov; NIAAA Contact:  Dr. Samir Zakhari, 301-443-0799, szakhari@mail.nih.gov

14-NS-101*     Reverse engineering human neurological disease.  It is now conceivable to reverse-engineer human neurological disease by generating and characterizing iPSCs from human control and patient populations. The relatively easy access of source tissue provides a means of elucidating patient-specific cell dysfunction or response to candidate therapeutics.  Research topics can include maximizing derivation efficiency, maintenance, or reproducibility, studies of cellular differentiation, screening bioactive agents, or profiling the molecular signature as well as the functional properties of cells from controls vs. patients.  There will be an emphasis on appropriate validation of iPS cells and their derivatives, evaluating the hetero/homogeneity of any cell populations to be screened and use of cellular assays relevant to normal development, organ function and disease. NINDS Contact: Dr. David Owens, 301-496-1447, do47h@nih.gov; NIAAA Contact: Dr. Samir Zakhari, 301-443-0799, szakhari@mail.nih.gov

(15) Translational Science

15-AA-101*    Determining If and How Adolescent Behaviors Affect Connections in the Developing Brain. The brain develops throughout adolescence and into early adulthood, and there is accumulating evidence that behaviors exhibited during this period can influence lifetime health and well-being. Research is needed to address the critical question – do these behaviors actually rewire the developing brain thereby creating vulnerability for a number of persistent health problems including mental health disorders, eating disorders and addiction? Contact:  Dr. Antonio Noronha, 301-443-7722, anoronha@mail.nih.gov

15-AA-102      Neurosteroids in alcohol intoxication, dependence, withdrawal and relapse.  Neurosteroids are important neuroactive substrates that have been demonstrated to be involved in several neurophysiological and disease processes, and alcohol has been shown to significantly increase neurosteroid levels in the brain. Accumulating evidence indicates that neurosteroids interact with neuroendocrine and multiple neurotransmission systems, and may play a crucial role in the pathophysiology of alcohol intoxication, dependence, withdrawal and relapse. Studies are needed to understand the effects and mechanisms of action of acute and chronic alcohol exposures on the homeostasis of neurosteroids and their interactions with the networks of neuroendocrine, neurotransmission and neural signal transduction systems.  This research is key to elucidating the molecular and cellular targets of ethanol, exploring the therapeutic potentials of agents acting on the neurosteroid system, and increasing our understanding of the results of animal and clinical studies. Contact person:  Dr. Qi-Ying Liu, 301 443-2678, liuqiy@mail.nih.gov

15-AA-103     Therapeutics and Therapeutic Screens for Fetal Alcohol Spectrum Disorders.  In utero exposure to ethanol can have a wide range of possible adverse developmental consequences, commonly referred to as Fetal Alcohol Spectrum Disorders (FASD). FASD may cause lifelong debilitating cognitive, behavioral, and emotional  impairments. Damage to the developing brain can occur at any stage of pregnancy, even before the woman is aware that she is pregnant. Efforts to encourage women to abstain from alcohol during pregnancy have not been completely successful; therefore, alternative approaches to prevention/amelioration are sought. Among the possibilities are prenatal and postnatal treatments with drugs, nutritional supplements, or gene therapies intended to block or reverse the harmful effects of alcohol.  Even if targets are identified, there are no high-throughput screens for identifying successful treatments of FASD. This initiative would provide funding to develop approaches that consider developmental neurobiology in pediatric drug development, and use models that are relevant to the developing brain that test safety and efficacy. The development of high-throughput screens or standardized model systems could identify new targets which have a significant impact on treatment of FASD and other neurodevelopmental disorders. Contact: Dr. Tom Greenwell, 301-443-1192, greenwellt@mail.nih.gov

15-AA-104     PTSD and Alcohol Dependence.  Epidemiological evidence indicates that a percentage of individuals exposed to trauma will go on to develop alcohol abuse and dependence.  Of immediate concern are the numbers of military personnel who experience post traumatic stress disorder and alcohol abuse.  Recent observations indicate that prazosin, an alpha 1 adrenergic receptor antagonist, has been effective in reducing alcohol consumption.  Medications to reverse trauma associated alcohol abuse could have an immediate impact on military veterans but also on civilian victims of trauma.  This initiative would support testing of promising molecular targets such as adrenergic receptors, CRF receptors, etc. for effectiveness in animal models. In addition the identification of new targets by examining the neurocircuits involved in fear response is encouraged. Contact person: Lindsey Grandison, Ph.D., 301-443-0606, lgrandis@mail.nih.gov

15-AA-105     Discovering New Medication Targets for Alcohol Dependence.  To advance development of medications that reduce alcohol drinking and sustain abstinence in alcohol dependent patients, this initiative will support projects evaluating novel pharmacological targets in animal models of alcohol dependence. Several targets have shown promise clinically and in preclinical studies, yet many additional targets (e.g., chemokines, stress and pain pathways) remain to be explored. Expanding the base of promising targets will stimulate testing and discovery of novel pharmacotherapies for alcohol dependence in the future.  Contact:  Dr. Mark Egli, 301-594-6382, megli@mail.nih.gov

15-AA-106     Functional Roles of Neuroimmune Factors in Mediating Binge Drinking.  Neuroimmune factors have significant impacts on both normal brain functions and a variety of neurological and behavioral disorders. Emerging data suggest that the physiological functions of neuroimmune factors, such as cytokines and chemokines, are not restricted to mediating neuroinflammatory responses. This paradigm shift offers a new framework for understanding the roles of neuroimmune factors in mediating alcohol drinking. Although a limited number of studies suggest that neuroimmune factors, particularly chemokines, mediate alcohol drinking behavior, it is essentially unknown how chemokines exert their effects. This initiative encourages research on the roles of chemokines in mediating alcohol drinking behavior.  Such research is expected to improve our understanding of the mechanisms of excessive drinking. Contact: Dr. Changhai Cui, 301-443-1678, Changhai@mail.nih.gov

15-AA-107     Refinements of Procedures for Diffusion Tensor Imaging in Rodent Models of Alcohol Dependence. Diffusion tensor imaging (DTI) has been used in human studies to visualize the direction of white matter tracts in the brain and to provide measurements related to the microstructural integrity of the fiber tracts in health and disease. Many of the technological advances in neuroimaging in humans have only recently been applied to small animal models such as mice and rats. Differences in head size and shape have been one of the issues that have impeded imaging in animals at an acceptable spatial resolution. A number of small animal models have been developed for the study of alcohol dependence and the application of neuroimaging techniques can be of great value in understanding the effects of alcohol in the brain. This initiative will support further development of procedures for DTI in small animals. Contact:  Dr. John Matochik, 301-451-7319, jmatochi@mail.nih.gov

15-AA-108     Molecular Mechanisms of Alcohol Dose Effects. It is well known that, in contrast to heavy alcohol drinking, moderate alcohol consumption can benefit human cognitive functions. Although there is extensive research on the damaging effects of alcohol on the brain, very little is known about neuronal mechanisms underlying the beneficial effects of moderate alcohol consumption.  Recent studies have shown that low concentrations of ethanol produce distinct effects on brain functions compared to high concentrations of ethanol. That is, low concentrations of ethanol modulate neurotransmitter receptors and signaling pathways differently compared to high concentrations of ethanol. Thus, depending on concentration, ethanol may exert differential effects on molecular targets in the brain. Further studies are sought on this topic to advance our understanding of the molecular and cellular mechanisms underlying beneficial versus deleterious effects of alcohol. Contact: Dr. Changhai Cui, 301-443-1678, Changhai@mail.nih.gov

15-NS-101*     Manipulating the blood-brain-barrier to deliver CNS therapies for Mental/Nervous System Disorders.  Neuroscience discoveries have led to promising therapeutic strategies for treatment of severe neurological disorders.  However, the blood brain barrier presents a major hurdle to delivering potentially exciting agents such as RNA therapies, genes, critical enzymes, antibodies, other molecular entities, or cell therapies.  The challenge is to develop potentially useful means of CNS drug targeting and delivery systems. NINDS Contact: Dr. Tom Jacobs,  301-496-1431, tj12g@nih.gov, NIAAA Contact: Dr. Samir Zakhari, 301-443-0799, szakhari@mail.nih.gov